Plasmodium falciparum is a deadly parasite that causes malaria in humans and is responsible for nearly 600,000 deaths very year. Malaria is endemic in large regions of the world infecting nearly ~300 million people every year. There are no effective vaccines against malaria and antimalarial drugs are the mainstay of treatment. Unfortunately, the parasite has gained resistance to all clinically available antimalarial drugs and these drug-resistant strains are spreading throughout the world. This is threatening all the progress that has been made against this disease in the last decade. Thus, it is imperative that we constantly identify potential drug targets to stay ahead of this nefarious disease. The parasites from the genus Plasmodium that cause malaria are single celled, eukaryotic pathogens. Since human cells are also eukaryotic, it can be tricky to develop drugs that specifically kill the parasite and don't have too many side effects. The parasitic Plasmodium cell is amazingly complex with two organelles that carry their own genetic material, the mitochondrion and a unique plastid of algal origin known as the apicoplast. The apicoplast is present only in the parasite and not in the human host. This makes it an ideal drug target since attacking the apicoplast will affect only the parasite and not the human host. In fact, some antibiotics have shown success as antimalarial drugs because they target essential biological processes in the apicoplast. However, the molecular mechanisms that drive the biology of this unique parasite organelle remain unknown, which hampers antimalarial drug development. The proposed studies target an important set of genes that we hypothesize to act as key regulators for the biogenesis of the apicoplast. Our preliminary data show that one of the targeted genes is essential for parasite growth underscoring the importance of this pathway in the biology of P. falciparum. We will apply genetic, cellular, and biochemical approaches to characterize the various roles that these genes play in the biogenesis of this essential parasite organelle. Attaining the aims of this proposal will uncover the novel biology of the apicoplast and identify parasite-specific essential proteins that can be targeted for antimalarial drug development.

Public Health Relevance

Parasites from the genus Plasmodium infect human red blood cells, causing a lethal disease called malaria, which affects hundreds of millions of people worldwide. The proposed research will study a unique organelle that is present only in the parasite. Understanding the key biological mechanisms that drive the biology of this unique parasite plastid will help us develop novel and specific antimalarial therapies, which are sorely needed because Plasmodium has developed resistance to all currently available antimalarial drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI128195-02
Application #
9394774
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2016-12-07
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Georgia
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Florentin, Anat; Cobb, David W; Fishburn, Jillian D et al. (2017) PfClpC Is an Essential Clp Chaperone Required for Plastid Integrity and Clp Protease Stability in Plasmodium falciparum. Cell Rep 21:1746-1756